Human clinical trials have failed to produce a disease modifying drug for treating late onset Alzheimer?s disease (AD) and ineffectual animal models are partly to blame. Our proposal addresses the large unmet need to produce an animal model of AD which will both increase our understanding of this disease as well as provide a model for pre-clinical drug testing. Unlike past models that relied on over expression of mutant genes from artificial promoters, we have used homologous recombination to create double and triple knock in (KI) mice using human genes that play a large role in AD. Current strategies also do not incorporate aging in their models which leaves out the single most important non-genetic risk factor in AD. In addition to aging we are adding chronic exposure to a Western diet (another prominent risk factor in AD) to our mouse models which also addresses the multifactorial nature of AD that is sorely lacking from current models. We have successfully created human NL-F APP/APOE3 (and E4), plus human TAU/APOE3 (and E4) double KI mice and recently APP/TAU/APOE3 (andE4) triple KI mice. Our preliminary data shows that feeding the double APP/APOE KI mice a Western diet for 6 months around midlife is insufficient to model AD as measured by amyloid beta burden, gliosis and synaptic markers. These results prompted us to extend both the dietary exposure and age at sacrifice which make up our two aims: Aim 1: Determine whether lifelong HFD exposure is sufficient to produce characteristics of AD in the double KI animal models, Aim 2: Determine whether lifelong HFD exposure is sufficient to produce characteristics of AD in the triple KI animal models. All of our models will be exposed to a Western diet from 2-18 (and 24) months of age, then phenotyped for biomarkers of AD (i.e. amyloid beta, abnormal tau, gliosis and neurodegeneration). We also plan to examine the brain lipid profile of these mice as preliminary data show deficiencies in essential fatty acids in the APOE4 mice. Thus, the hypothesis we plan to test is that APOE4 carriers are at increased risk for AD due to insufficient uptake of essential fatty acids required for maintaining neuronal health. Most importantly, if our ideas are correct, we will have produced an invaluable model of AD that the entire research community can use to develop new treatments for AD.